This study aims to determine the genetic factors that control the timing of pubertal onset. The specific aims include; 1) genetic control of the timing of puberty is polygenic; 2) the genetic influence is likely mediated by common sequence variants; 3) some of these sequence variants occur in previously identified physiologically relevant genes. Background: The factors that control the timing of the onset of puberty are not well understood. Although a variety of environmental factors (such as socioeconomic status, nutrition, and geography) as well as biologic parameters (such as body composition and general health) are known to influence the timing of puberty, genetic factors also play an important role. Early and delayed puberal onset are familial traits, age of menarche displays concordance among monozygotic and dizygotic twins, development of secondary sexual characteristics varies among racial groups, and a few cases of familial central precocious puberty have been described. Regulation of the timing of puberty is, however, unlikely to exhibit classic Mendelian inheritance or be attributable to a single locus; rather it is likely to be a complex genetic trait that is modulated by variations in multiple genes. A new area in human genetics is the study of allelic variations and their association with susceptibility to common disease and expession of complex traits. Although DNA variants that cause monogenic disease are usually rare, it is believed that th4e genetic variants involved in polygenic disease and complex traits, which may have had little selective pressure against them, are common within the population. The presence of particular common variants or combination of variants within an individual's genome likely confers the genetic predisposition to disease and modulates complex traits. These common variants, which may or may not lead to changes in the protein's amino acid sequence,are arbitrarily defined as polymorphism, when they occur in more than 1% of the population. Multiple examples of such polymorphisms affecting disease susceptibility have recently been reported, including sequence variation of the factor VII gene that influence the risk of myocardial infaction, polymorphism in the cholesterol ester tranfer protein gene that affect progression of coronary atherosclerosis, variations in chemokine receptors that confer protection against HIV-1 and the presence of the apolipoptrotien E type 4 allele that significantly increases the risk of Alzheimer's diseae. The discovery of allelic variation is now expanding to encompass factors that modulate the expression of complex traits. It is the broad goal of this proposal to focus this modern genetic theory and its associated techniques on elucidating the role that polymorphisms play in controlling the onset of puberty in humans.